U.S. Route 421 in Indiana

US 421 enters Indiana from Kentucky over the Ohio River. After crossing the Ohio River US 421 has a short concurrency with State Road 56 (SR 56). After the concurrency with SR 56 ends US 421 becomes a four-lane highway. US 421 has an intersection with State Road 62 (SR 62). North of Madison US 421 becomes a two-lane highway, heading north then northeast. US 421 heads towards Versailles, passing through an intersection with State Road 250 (SR 250). In Versailles US 421 has a concurrency with State Road 129 that ends at U.S. Route 50 (US 50). US 421 heads west out of Versailles concurrent with US 50. West of Versailles US 421 heads northwest, towards Greensburg. US 421 passes through Osgood and Napoleon, passing through intersections with State Road 350 (SR 350) and SR 229. US 421 enters Greensburg on the southeast side of town and heads to the northwest side of town. In Greensburg US 421 is concurrent with State Road 46 (SR 46) and intersects State Road 3 (SR 3). On the northwest side of Greensburg US 421 joins Interstate 74 (I-74). I-74/US 421 heads northwest towards Indianapolis, passing near Shelbyville. Near Shelbyville I-74/US 421 has interchanges with State Road 44 (SR 44) and State Road 9 (SR 9). I-74/US 421 enters Indianapolis on the southeast side of the city. US 421 heads north and west around Indianapolis, concurrent with Interstate 465.

US 421 is concurrent with I-465, until the northwest side of the city. US 421 leaves I-465 heading northwest. US 421 becomes a two-lane highway, heading through intersections with State Road 32 (SR 32), State Road 47 (SR 47), State Road 38 (SR 38), and State Road 29 (SR 29), and has a concurrency with State Road 28 (SR 28). US 421 and SR 28 enter Frankfort heading west; the concurrency ends when US 421 heads north concurrent with State Road 38 (SR 38) and State Road 39 (SR 39). US 421/SR 38/SR 39 heads northwest out of Frankfort, and 5 miles (8.0 km) later SR 38 heads due west. US 421/SR 39 heads northwest towards Delphi passing through an intersection with State Road 26 (SR 26). In Delphi US 421/SR 39 are concurrent with State Road 25 (SR 25). US 421/SR 39 heads northwest out of Delphi passing through Pittsburg. West of Pittsburg US 421/SR 39 heads due north towards Monticello. In Monticello the concurrency with SR 39 ends with SR 39 heading east on U.S. Route 24 and US 421 heading west on US 24. US 24/US 421 heads north towards Reynolds, where US 24 heads west and US 421 heads due north.

After the concurrency with US 24, US 421 runs into mostly rural areas as it leaves White County and enters Pulaski County, turning from a northwest trajectory to a due north one. It enters the tiny town of Francesville where it shares a couple of junctions and concurrencies. Just before leaving Pulaski County, US 421 crosses into the unincorporated community of Radioville. After that, it exits Pulaski County and enters Starke County, which also marks the border of Eastern Time and Central Time Zones.

US 421 heads north towards Michigan City, passing through Monon, Wanatah, and Westville. US 421 has intersections with State Road 16 (SR 16), State Road 114 (SR 114), State Road 143 (SR 143), State Road 8 (SR 8), and U.S. Route 30 (US 30). US 421 has concurrencies with State Road 14 (SR 14), State Road 10 (SR 10), U.S. Route 6 (US 6), and State Road 2 (SR 2). US 421 has interchanges with Interstate 80/Interstate 90 and Interstate 94. US 421's northern terminus is at U.S. Route 20 (US 20) in Michigan City.

US 421 passed through downtown Madison and headed northwest out of Madison. A new route was built east of the old route. The old route was designated State Road 107 until it was decommissioned.

US 421 entered Indianapolis on the southeast side of the city and went through downtown. US 421 was routed on Southeastern Avenue, Washington Street, Northwestern Avenue (now Martin Luther King Jr. Street), and Michigan Road.

US 421 went through Michigan City to U.S. Route 12 (US 12) near Lake Michigan. Then INDOT moved the northern terminus of US 421 south to US 20, on the south side of Michigan City.